Skip to main content
SpringerLink
Log in

Infratentorial IDH-mutant astrocytoma is a distinct subtype

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Diffuse IDH-mutant astrocytic tumors are rarely diagnosed in the cerebellum or brainstem. In this multi-institutional study, we characterized a series of primary infratentorial IDH-mutant astrocytic tumors with respect to clinical and molecular parameters. We report that about 80% of IDH mutations in these tumors are of non-IDH1-R132H variants which are rare in supratentorial astrocytomas. Most frequently, IDH1-R132C/G and IDH2-R172S/G mutations were present. Moreover, the frequencies of ATRX-loss and MGMT promoter methylation, which are typically associated with IDH mutations in supratentorial astrocytic tumors, were significantly lower in the infratentorial compartment. Gene panel sequencing revealed two samples with IDH1-R132C/H3F3A-K27M co-mutations. Genome-wide DNA methylation as well as chromosomal copy number profiling provided further evidence for a molecular distinctiveness of infratentorial IDH-mutant astrocytomas. Clinical outcome of patients with infratentorial IDH-mutant astrocytomas is significantly better than that of patients with diffuse midline gliomas, H3K27M-mutant (p < 0.005) and significantly worse than that of patients with supratentorial IDH-mutant astrocytomas (p = 0.028). The presented data highlight the very existence and distinctiveness of infratentorial IDH-mutant astrocytomas that have important implications for diagnostics and prognostication. They imply that molecular testing is critical for detection of these tumors, since many of these tumors cannot be identified by immunohistochemistry applied for the mutated IDH1-R132H protein or loss of ATRX.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Abbas S, Lugthart S, Kavelaars FG, Schelen A, Koenders JE, Zeilemaker A, van Putten WJ, Rijneveld AW, Lowenberg B, Valk PJ (2010) Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood 116:2122–2126. https://doi.org/10.1182/blood-2009-11-250878

    Article  CAS  PubMed  Google Scholar 

  2. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, Pollock R, O'Donnell P, Grigoriadis A, Diss T et al (2011) IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224:334–343. https://doi.org/10.1002/path.2913

    Article  CAS  PubMed  Google Scholar 

  3. Amorim JP, Santos G, Vinagre J, Soares P (2016) The role of ATRX in the alternative lengthening of telomeres (ALT) phenotype. Genes (Basel). https://doi.org/10.3390/genes7090066

    Article  PubMed Central  Google Scholar 

  4. Arita H, Narita Y, Fukushima S, Tateishi K, Matsushita Y, Yoshida A, Miyakita Y, Ohno M, Collins VP, Kawahara N et al (2013) Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol 126:267–276. https://doi.org/10.1007/s00401-013-1141-6

    Article  CAS  PubMed  Google Scholar 

  5. Bady P, Sciuscio D, Diserens AC, Bloch J, van den Bent MJ, Marosi C, Dietrich PY, Weller M, Mariani L, Heppner FL et al (2012) MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status. Acta Neuropathol 124:547–560. https://doi.org/10.1007/s00401-012-1016-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597–602. https://doi.org/10.1007/s00401-008-0455-2

    Article  CAS  PubMed  Google Scholar 

  7. Behling F, Steinhilber J, Tatagiba M, Bisdas S, Schittenhelm J (2015) IDH1 R132H mutation in a pilocytic astrocytoma: a case report. Int J Clin Exp Pathol 8:11809–11813

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP, Parrens M, Martin A, Xerri L, Brousset P et al (2012) IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood 119:1901–1903. https://doi.org/10.1182/blood-2011-11-391748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cairns RA, Mak TW (2013) Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov 3:730–741. https://doi.org/10.1158/2159-8290.CD-13-0083

    Article  CAS  PubMed  Google Scholar 

  10. Cancer Genome Atlas Research N, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, Cooper LA, Rheinbay E, Miller CR, Vitucci M et al (2015) Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med 372:2481–2498. https://doi.org/10.1056/NEJMoa1402121

    Article  CAS  Google Scholar 

  11. Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, Koelsche C, Sahm F, Chavez L, Reuss DE et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474. https://doi.org/10.1038/nature26000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dunford A, Weinstock DM, Savova V, Schumacher SE, Cleary JP, Yoda A, Sullivan TJ, Hess JM, Gimelbrant AA, Beroukhim R et al (2017) Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias. Nat Genet 49:10–16. https://doi.org/10.1038/ng.3726

    Article  CAS  PubMed  Google Scholar 

  13. Ebrahimi A, Skardelly M, Bonzheim I, Ott I, Muhleisen H, Eckert F, Tabatabai G, Schittenhelm J (2016) ATRX immunostaining predicts IDH and H3F3A status in gliomas. Acta Neuropathol Commun 4:60. https://doi.org/10.1186/s40478-016-0331-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ellezam B, Theeler BJ, Walbert T, Mammoser AG, Horbinski C, Kleinschmidt-DeMasters BK, Perry A, Puduvalli V, Fuller GN, Bruner JM et al (2012) Low rate of R132H IDH1 mutation in infratentorial and spinal cord grade II and III diffuse gliomas. Acta Neuropathol 124:449–451. https://doi.org/10.1007/s00401-012-1011-7

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, Felsberg J, Wolter M, Mawrin C, Wick W et al (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 118:469–474. https://doi.org/10.1007/s00401-009-0561-9

    Article  PubMed  Google Scholar 

  16. Heaphy CM, Subhawong AP, Hong SM, Goggins MG, Montgomery EA, Gabrielson E, Netto GJ, Epstein JI, Lotan TL, Westra WH et al (2011) Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am J Pathol 179:1608–1615. https://doi.org/10.1016/j.ajpath.2011.06.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hong B, Banan R, Christians A, Nakamura M, Lalk M, Lehmann U, Hartmann C, Krauss JK (2018) Cerebellar glioblastoma: a clinical series with contemporary molecular analysis. Acta Neurochir (Wien) 160:2237–2248. https://doi.org/10.1007/s00701-018-3673-y

    Article  Google Scholar 

  18. Ichimura K, Pearson DM, Kocialkowski S, Backlund LM, Chan R, Jones DT, Collins VP (2009) IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol 11:341–347. https://doi.org/10.1215/15228517-2009-025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ida CM, Lambert SR, Rodriguez FJ, Voss JS, Mc Cann BE, Seys AR, Halling KC, Collins VP, Giannini C (2012) BRAF alterations are frequent in cerebellar low-grade astrocytomas with diffuse growth pattern. J Neuropathol Exp Neurol 71:631–639. https://doi.org/10.1097/NEN.0b013e31825c448a

    Article  CAS  PubMed  Google Scholar 

  20. Javadi SA, Hartmann C, Walter GF, Banan R, Samii A (2018) IDH1 Mutation in brain stem glioma: case report and review of literature. Asian J Neurosurg 13:414–417. https://doi.org/10.4103/1793-5482.228540

    Article  PubMed  PubMed Central  Google Scholar 

  21. Koelsche C, Sahm F, Capper D, Reuss D, Sturm D, Jones DT, Kool M, Northcott PA, Wiestler B, Bohmer K et al (2013) Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. Acta Neuropathol 126:907–915. https://doi.org/10.1007/s00401-013-1195-5

    Article  CAS  PubMed  Google Scholar 

  22. Korshunov A, Casalini B, Chavez L, Hielscher T, Sill M, Ryzhova M, Sharma T, Schrimpf D, Stichel D, Capper D et al (2019) Integrated molecular characterization of IDH-mutant glioblastomas. Neuropathol Appl Neurobiol 45:108–118. https://doi.org/10.1111/nan.12523

    Article  CAS  PubMed  Google Scholar 

  23. Leeper HE, Caron AA, Decker PA, Jenkins RB, Lachance DH, Giannini C (2015) IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas. Oncotarget 6:30295–30305. https://doi.org/10.18632/oncotarget.4497

    Article  PubMed  PubMed Central  Google Scholar 

  24. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Ellision DW, Figarella-Branger D, Reifenberger G, von Deimling A (2016) WHO classification and grading of tumours of the central nervous system. IARC Press; International Agency for Research on Cancer, City

  25. Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS (2018) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Neuro Oncol 20:1–86. https://doi.org/10.1093/neuonc/noy131

    Article  Google Scholar 

  26. Picca A, Berzero G, Bielle F, Touat M, Savatovsky J, Polivka M, Trisolini E, Meunier S, Schmitt Y, Idbaih A et al (2018) FGFR1 actionable mutations, molecular specificities, and outcome of adult midline gliomas. Neurology 90:e2086–e2094. https://doi.org/10.1212/WNL.0000000000005658

    Article  CAS  PubMed  Google Scholar 

  27. Porkholm M, Raunio A, Vainionpaa R, Salonen T, Hernesniemi J, Valanne L, Satopaa J, Karppinen A, Oinas M, Tynninen O et al (2018) Molecular alterations in pediatric brainstem gliomas. Pediatr Blood Cancer. https://doi.org/10.1002/pbc.26751

    Article  PubMed  Google Scholar 

  28. Pusch S, Schweizer L, Beck AC, Lehmler JM, Weissert S, Balss J, Miller AK, von Deimling A (2014) D-2-Hydroxyglutarate producing neo-enzymatic activity inversely correlates with frequency of the type of isocitrate dehydrogenase 1 mutations found in glioma. Acta Neuropathol Commun 2:19. https://doi.org/10.1186/2051-5960-2-19

    Article  PubMed  PubMed Central  Google Scholar 

  29. Reinhardt A, Stichel D, Schrimpf D, Koelsche C, Wefers AK, Ebrahimi A, Sievers P, Huang K, Casalini MB, Fernandez-Klett F et al (2019) Tumors diagnosed as cerebellar glioblastoma comprise distinct molecular entities. Acta Neuropathol Commun 7:163. https://doi.org/10.1186/s40478-019-0801-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Reuss DE, Sahm F, Schrimpf D, Wiestler B, Capper D, Koelsche C, Schweizer L, Korshunov A, Jones DT, Hovestadt V et al (2015) ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an "integrated" diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. Acta Neuropathol 129:133–146. https://doi.org/10.1007/s00401-014-1370-3

    Article  CAS  PubMed  Google Scholar 

  31. Reyes-Botero G, Giry M, Mokhtari K, Labussiere M, Idbaih A, Delattre JY, Laigle-Donadey F, Sanson M (2014) Molecular analysis of diffuse intrinsic brainstem gliomas in adults. J Neurooncol 116:405–411. https://doi.org/10.1007/s11060-013-1312-2

    Article  CAS  PubMed  Google Scholar 

  32. Rohrich M, Koelsche C, Schrimpf D, Capper D, Sahm F, Kratz A, Reuss J, Hovestadt V, Jones DT, Bewerunge-Hudler M et al (2016) Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathol 131:877–887. https://doi.org/10.1007/s00401-016-1540-6

    Article  CAS  PubMed  Google Scholar 

  33. Sahm F, Schrimpf D, Jones DT, Meyer J, Kratz A, Reuss D, Capper D, Koelsche C, Korshunov A, Wiestler B et al (2016) Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets. Acta Neuropathol 131:903–910. https://doi.org/10.1007/s00401-015-1519-8

    Article  CAS  PubMed  Google Scholar 

  34. Sahm F, Schrimpf D, Stichel D, Jones DTW, Hielscher T, Schefzyk S, Okonechnikov K, Koelsche C, Reuss DE, Capper D et al (2017) DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol 18:682–694. https://doi.org/10.1016/S1470-2045(17)30155-9

    Article  CAS  PubMed  Google Scholar 

  35. Shirahata M, Ono T, Stichel D, Schrimpf D, Reuss DE, Sahm F, Koelsche C, Wefers A, Reinhardt A, Huang K et al (2018) Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol 136:153–166. https://doi.org/10.1007/s00401-018-1849-4

    Article  CAS  PubMed  Google Scholar 

  36. Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164. https://doi.org/10.1093/nar/gkq603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Watanabe T, Nobusawa S, Kleihues P, Ohgaki H (2009) IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174:1149–1153. https://doi.org/10.2353/ajpath.2009.080958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773. https://doi.org/10.1056/NEJMoa0808710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by German Cancer Aid (70112371, 70112188). AvD, DER, DTWJ, SMP, CHM, WW and FS were supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 1389). FS is fellow of the Else Kröner Excellence Program of the Else Kröner-Fresenius Stiftung (EKFS). LS is participant in the BIH‐Charité Clinical Scientist Program funded by the Charité and the BIH. Graphical illustration in Fig. 1 are derived from Servier Medical Art by Servier (https://smart.servier.com/) licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).

Author information

Author notes

  1. Christian Hartmann and David E. Reuss contributed equally to this study.

Authors and Affiliations

  1. Department of Neuropathology, Institute of Pathology, Hannover Medical School (MHH), Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Rouzbeh Banan, Anja Bleck & Christian Hartmann

  2. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany

    Damian Stichel, Abigail Suwala, Annekathrin Reinhardt, Daniel Schrimpf, Felix Sahm, Andreas von Deimling & David E. Reuss

  3. Department of Neurosurgery, Hannover Medical School, Hannover, Germany

    Bujung Hong

  4. Institute of Pathology, Hannover Medical School, Hannover, Germany

    Ulrich Lehmann

  5. Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany

    Abigail Suwala, Annekathrin Reinhardt, Daniel Schrimpf, Felix Sahm, Andreas von Deimling & David E. Reuss

  6. Institute of Pathology, Klinikum Bamberg, Klinikum, Germany

    Rolf Buslei

  7. Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany

    Christine Stadelmann

  8. Department of Pediatric Oncology and Hematology, University of Greifswald, Greifswald, Germany

    Karoline Ehlert

  9. Institute of Neuropathology, University of Freiburg, Freiburg, Germany

    Marco Prinz

  10. Institute of Neuropathology, University of Gießen, Gießen, Germany

    Till Acker

  11. Department of Neuropathology, University of Tübingen, Tübingen, Germany

    Jens Schittenhelm

  12. Department of Radiation Oncology and Radiotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany

    David Kaul

  13. Department of Neuropathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany

    Leonille Schweizer & David Capper

  14. German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Partner Site Berlin, Heidelberg, Germany

    Leonille Schweizer & David Capper

  15. Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany

    Patrick N. Harter

  16. German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Frankfurt, Germany

    Patrick N. Harter

  17. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Patrick N. Harter

  18. Frankfurt Cancer Institute (FCI), Frankfurt am Main, Frankfurt, Germany

    Patrick N. Harter

  19. Department of Neurosurgery, University Hospital Mannheim, University of Heidelberg, Heidelberg, Germany

    Nima Etminan

  20. German Cancer Consortium (DKTK), Heidelberg, Germany

    David T. W. Jones, Stefan M. Pfister, Wolfgang Wick & Andreas von Deimling

  21. Hopp Childrens Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    David T. W. Jones & Stefan M. Pfister

  22. Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany

    David T. W. Jones

  23. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Stefan M. Pfister

  24. Department of Pediatric Oncology and Hematology, University Hospital Heidelberg, Heidelberg, Germany

    Stefan M. Pfister

  25. Department of Neurosurgery, Division of Experimental Neurosurgery, University Hospital, Heidelberg, Germany

    Christel Herold-Mende

  26. Neurology Clinic, University of Heidelberg Medical Center, Heidelberg, Germany

    Wolfgang Wick

Authors
  1. Rouzbeh Banan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Damian Stichel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anja Bleck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bujung Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ulrich Lehmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Abigail Suwala
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Annekathrin Reinhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daniel Schrimpf
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rolf Buslei
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christine Stadelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Karoline Ehlert
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Marco Prinz
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Till Acker
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jens Schittenhelm
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. David Kaul
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Leonille Schweizer
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. David Capper
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Patrick N. Harter
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Nima Etminan
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. David T. W. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Stefan M. Pfister
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Christel Herold-Mende
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Wolfgang Wick
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Felix Sahm
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Andreas von Deimling
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Christian Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. David E. Reuss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Christian Hartmann or David E. Reuss.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Banan, R., Stichel, D., Bleck, A. et al. Infratentorial IDH-mutant astrocytoma is a distinct subtype. Acta Neuropathol 140, 569–581 (2020). https://doi.org/10.1007/s00401-020-02194-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-020-02194-y

Keywords

Search

Navigation